Method for fabrication of additively manufactured, self-gelling structures and their use

ABSTRACT

Disclosed are Self-Gelling materials and structures or materials or structures having one or more self-gelling components that overcome existing gel limitations due to hydrogel localization for medical applications by providing, for example, 1) microstructurally, or physically, anchored characteristics to help localize the gel, and the overall printed, or otherwise formed structure, giving structural form to the gel that allows the gel to be localized within the body, and even sutured in place, and mitigates gel migration and extends its residence time; 2) to provide an underlying 3D printed structure to help contain and support the gel after implantation; and more. Self-Gelling 3D printed structures may be further processed via milling to yield deconstructed scaffold micro-granules, with the composition and nano-/micro- structure of the original larger structure. Deconstructed scaffold micro-granules may be hydrated to form a micro-granule embedded gel network that can be injected, giving form to injectable gels.

This patent application claims priority to and benefit of U.S.Provisional Application No. 63/212,420, filed Jun. 18, 2021, which isincorporated herein by reference.

BACKGROUND

This disclosure relates to hydrogel localization and stabilization.

Hydrogels are useful base materials for medical and other applications,including, for example, for tissue healing and regeneration, drugdelivery, cell delivery, encapsulation of implantable devices andbioelectronics. They are physically similar to the natural matrix andmake up of the human body—a loose, nano network containing hydrogen- orelectrostatically-bound water-based media (i.e., much of the human bodyis gel-like). Because of the physical similarities to biologicalsystems, hydrogels have numerous medical applications, including but notlimited to: tissue repair, drug delivery, gene delivery, cell delivery,and inflammation reduction. However, hydrogels intended for medical use,particularly those designed for fixed placement in the body and/orinjection, suffer from numerous drawbacks, which include that they 1)are difficult to localize (gels will easily move and become delocalizedas a result of mechanical stress after implantation) and 2) tend tobreak, tear, disperse, or fall apart due to movement resulting from theinability to be localized. These technical deficiencies greatly limitthe effectiveness of medical hydrogels across applications.Additionally, hydrogels must often be prepared onsite, in the operatingroom, and/or in the clinician's office immediately prior to use—addingprocedure time and cost as well as increasing the likelihood forpreparation and application mistakes.

SUMMARY

The materials and structures having one or more self-gelling componentsas defined in this invention in various embodiments offer improvedperformance over existing, non-microstructurally anchored gels because,for example, 1) the microstructurally, or physically, anchoredcharacteristics help localize the gel, and the overall printed, orotherwise formed structure, give structural form to the gel—allowing thegel to be localized within the body, and even sutured inplace—mitigating gel migration, increasing resistance to mechanicalforces, and extending its residence time; 2) the underlying 3D printedscaffold or deconstructed 3D printed scaffold particle materials'designed macro-, and inherent micro- and nanostructure structures helpcontain and support the gel after implantation or injection; and/or 3)the pre-activated Gelling Powder containing 3D-printed scaffold materialis shelf-stable and can be cut, trimmed, compressed, delivered viacannula, etc., for example, prior to hydration—allowing it be placed andhydrated with surrounded blood, media, plasma, etc. upon implantation orinjection—greatly increasing the device's ability to integrate and healsurrounding tissue. As used herein, one or more self-gelling components,or one or more self-gelling powder components, refers to one or more ofthe same self-gelling component and/or one or more of differentself-gelling components. The presently disclosed materials having one ormore self-gelling components are distinct from injectable hydrogels aswell as implanted 3D printed hydrogels, which are much slower to absorbsurrounding biological components because they are already hydrated.Additionally, the underlying, nano- and micro-porous polymer mesh, inthe form of a 3D printed structure or deconstructed 3D printedstructure, help maintain implant form or injectable volume,respectively, improving localization better than polymer or compositemeshes that have had gels added to them prior to implantation, where thegel component is not anchored within the nano-/micro-structure of thepolymer network and is instead just loosely encapsulating the mesh.

A Gelling Powder containing material, or structure, is disclosed, wherethe Gelling Powder is essentially anhydrous, and is intended to begelled after generating, or forming, a 3D-printed structure and/or afterfabrication of deconstructed granules. In other words, the GellingPowder is gelled only upon being activated in a post-processingtreatment, as further disclosed below. The Gelling Powder containingmaterial, and underlying matrix, or mesh, structure, further expandsupon hydration, that is the gelation, or upon being otherwise activated,because of the embedded Gelling Powder expanding and pushing against apolymer microporous matrix, or mesh, network. Because the Gelling Powderis essentially anhydrous, gelling powder comprising deconstructedscaffold micro-granules may additionally be achieved by milling ofextruded or otherwise formed material derived from the Gelling Powdercomprising ink for further incorporation into a subsequent inkcomposition, or a deconstructed scaffold micro-granule containingGelling Powder (referred to herein more generally as “DeconstructedScaffold Gelling Granules”). The micro-granules, themselves, arediscrete particles comprised of discrete particles of gelling powderembedded within a porous biodegradable polymer matrix or, in otherwords, the deconstructed scaffold micro-granule is comprised of thebiodegradable polymer matrix with embedded gelling particle. Granule isunderstood as being larger than a powder particle and the DeconstructedGelling

Granule is a micro-granule produced from a deconstructed scaffold thatotherwise contains gelling powder.

The present disclosure also includes a 3D printed structure having oneor more self-gelling components, the 3D printed structure comprising aporous polymer or polymer-composite matrix, or mesh, structureencapsulating, or integrating, a dry gelling powder and/or adeconstructed scaffold micro-granule (i.e., Gelling Powder and/orDeconstructed Scaffold Gelling Granule) that is shelf-stable in dry formwherein the gelling powder component of the structure is configured togel when contacted with an aqueous solution. The structure mayadditionally comprise micro and/or nano particles embedded within theporous polymer matrix, or mesh, structure in dry form, which becomefurther internally saturated and encapsulated by gel after the structureis exposed to an aqueous solution. The micro and/or nano particles maybe one or more of electrically conductive materials, ceramic materials,metallic materials, and biologically derived materials. The structuremay further additionally comprise drugs, small molecules, RNA, and/orDNA and their derivatives. The polymer matrix, or mesh, structure may bea biocompatible polymer matrix, or mesh, structure. The dry gellingpowder and/or the deconstructed scaffold micro-granule (i.e., GellingPowder and/or Deconstructed Scaffold Gelling Granule) is disposed withinthe porous microstructure of the biocompatible polymer matrix, or mesh,structure. In examples, the dry gelling powder containing ormicro-granule containing 3D printed structures (containing eitherGelling Powders and/or Deconstructed Scaffold Gelling Granules) may bewater washed or washed in an aqueous solution, where the gelling powdersundergo gelation to form a voluminous gel and become microstructurally,or physically, anchored within the interconnected nano- andmicro-porosity of the porous biocompatible polymer matrix, or mesh,structure. As referred to herein, nano- and micro-porosity refers toporous properties that range from a nano-scale to a micro-scale. In suchexamples herein, the porosity may be on both the nano-scale and themicro-scale. In such examples herein, the porosity may be on thenano-scale only. In such examples herein, the porosity may be on amicro-scale only. The matrix, or mesh, structure, as well as theDeconstructed Scaffold Gelling Granules are very porous. The pore sizesof these materials are of the said nano- and micro-porosity, oralternatives, as noted here. It is noted, however, that the pores of theporous biocompatible polymer matrix are not larger than theDeconstructed Scaffold Gelling Granules themselves. In particularexamples, the pores of the porous biocompatible polymer matrix are notlarger than 20 μm in size.

Also described is an ink composition for extrusion-based 3D printing ofa 3D printed structure having one or more self-gelling powdercomponents, the ink composition comprises a solvent-based biocompatiblepolymer comprising and maintaining a dry gelling powder that isencapsulated, or integrated, within the biocompatible polymer that isconfigured after printing to be washed in alcohol, remain shelf-stablein a dry form upon drying, and gel upon hydration in an aqueoussolution. In examples, the ink composition is not and does not comprisea hydrogel. In examples, the dry gelling powder has an average particlesize of less than 100 μm. In examples, the dry gelling powder componentis used in combination with one or more electrically conductivematerials, ceramic materials, metallic materials, or biologicallyderived materials (such as, for example, proteins, peptides,extracellular matrix, etc.). These other materials may also be in powderform but may be different than or distinct from the dry gelling powderand may be provided in addition to the dry gelling powders. Theseparticles may be the above-mentioned micro and/or nano particles. Themicro and/or nano particles may be any composition that does notdissolve in the primary solvent used in the ink, dichloromethane, or thealcohol solutions utilized during the washing step. In an example, anadditional powder component comprising one or more of nano-scale andmicro-scale materials that may be one or more of electrically conductivematerials, ceramic materials, metallic materials, and biologicallyderived materials are suspended in the solvent-based polymer extrusion.

Also described is a method of forming a structure having one or moreself-gelling components comprising the steps of:

-   -   combining a solvent-based polymer with a dried gelling powder to        form an ink and extruding the ink to form a structure having an        interconnected nano- and micro-porous polymer matrix, or mesh,        with embedded gelling powder;    -   washing the structure having the nano- and micro-porous polymer        matrix, or mesh, with embedded gelling powder through a series        of alcohol solution and water washes to remove residual        solvents;    -   activating and gelling the dried gelling powder in the step of        washing where the dried gelling powder absorbs water and        transforms into a gel which fills, exudes from, and encapsulates        the microporous polymer matrix, or mesh, structure;    -   drying the gel containing an encapsulated microporous polymer        matrix, or mesh, into a shelf-stable structure and in a dry        form; and    -   hydrating the shelf-stable structure in an aqueous based        solution.

The solvent-based polymer may be a solvent-based biocompatible polymer.The dry microporous polymer matrix, or mesh, with embedded gellingpowder may additionally be mechanically milled to produce gelling powdercontaining deconstructed scaffold micro-granules or, in other words, aDeconstructed Scaffold Gelling Granule. The step of hydrating may be thestep of implanting the shelf-stable structure into a patient. The methodmay further comprise the steps of:

-   -   creating an interconnected solid-gel suspension by hydrating the        Deconstructed Scaffold Gelling Granule connected by and        suspended within a gel network (micro-granular embedded gel) by        hydrating the structure having a microporous polymer matrix with        an embedded dried gelling powder; and    -   injecting the interconnected solid-gel suspension through a        syringe forming a distinct structure comprising a continuously        connected hydrogel anchored within and surround discrete units        of nano- and micro-porous biocompatible polymer particles before        the step of washing wherein the gel is microstructurally, or        physically, anchored within the nano- and micro-porous        biocompatible polymer particles after the step of hydrating.

The present disclosure describes another 3D printed structure having oneor more self-gelling components. This 3D-printed structure comprises apolymer matrix, or mesh, structure encapsulating, or integrating, ananhydrous washed and absorbent dry gelling powder of discrete,dehydrated, particles that are lyophilized and are configured to gel inan aqueous based solution. The dry gelling powder may be configured tobe anchored within a microstructure of the polymer matrix, or mesh,structure upon gelation. In other words, the dry gelling powder isembedded within the microstructure of the polymer matrix, or mesh, andonce the gelling powder is exposed to water, and thereafter gels, theresulting gel is anchored to the position of the originating dry gellingpowder particle, which is within the nano- and micro-porous non-gellingpolymer microstructure. The gel encapsulates and surrounds the polymermicrostructure, but also permeates and is anchored within it. Theself-gelling 3D printed structure may further comprise micro and/or nanoparticles configured to be embedded within the microporous polymermatrix, or mesh, structure by being encapsulated in a solid-gelsuspension encapsulated, or integrated, within the polymer matrix, ormesh, structure upon gelation. The polymer matrix, or mesh, structuremay be a biocompatible polymer matrix, or mesh, structure. In examples,the ink composition itself is not and does not comprise a gel.

The micro and/or nano particles may be embedded within the porouspolymer matrix, or mesh, similar to the gelling powder. Upon hydrationthe gelling powder turns into gel and expands, which fills andencompasses the porous polymer matrix, or mesh, as well as encompassingthe surrounding micro and/or nano particles. The length scale of themicro and/or nano particles is such that the development and expansionof the gel powder upon hydration actually moves/pushes the micro and/ornano particles through the porous polymer network. In one example, thenanoparticles move with the hydrated gel while the microparticles do notmove or do not significantly move with the expanding gel.

The present disclosure describes another ink composition for printing a3D printed structure. The ink composition comprises a solvent-basedpolymer encapsulating, or integrating, an anhydrous gelling powder ofdiscreate particles wherein the gelling powder is configured to gel inan aqueous based solution after extrusion. In other words, the gellingpowder is extruded with the ink and does not gel until after extrusion,or a 3D printed structure is formed. The gelling powder is extruded withthe ink and does not gel until after extrusion because it does not geluntil being exposed to an aqueous environment. Thereafter, the 3Dprinted structure may be exposed to an aqueous based solution and thegelling powder gels. In other words, the gelling powder containing inkdoes not gel during extrusion, after extrusion, or after formation of a3D printed structure until the 3D printed structure is exposed to anaqueous environment. The ink composition may further comprise microand/or nano particles configured to be embedded within the microporouspolymer matrix, or mesh, with embedded gelling powder structure. Thesolvent-based polymer is a solvent-based biocompatible polymer. Inexamples, the ink composition is not and does not comprise a gel.Further, in examples, the 3D printed structure is not and does notcomprise a gel. In examples, the dry gelling powder has an averageparticle size of less than 100 μm. In some examples, the dry gellingpowder component is used in combination with one or more electricallyconductive materials, ceramic materials, metallic materials, drugs,synthetic chemistries, or biologically derived materials.

Also described is a method of forming a polymer structure with one ormore self-gelling components comprising the steps of:

combining a solvent-based microporous polymer with a dried gellingpowder to form an ink and extruding the ink to form a microporouspolymer with embedded gelling powder structure;

-   -   washing the microporous polymer with embedded gelling powder        structure in a non-aqueous solvent or anhydrous wash to prevent        pre-gelling;    -   drying the washed microporous polymer with embedded gelling        powder structure to form a dry shelf-stable structure; and    -   activating and gelling the gelling powder component of the dry        shelf-stable structure by hydrating the dry shelf-stable        structure in an aqueous based solution where the gelling of the        dried gelling powder component absorbs water or a primary        aqueous solution (e.g., including but not limited to water,        blood, cell suspension, biological plasma, drug containing        solutions, or the like), gels, and expands the microporous        polymer matrix, or mesh, component of the dry shelf-stable        structure

The solvent-based polymer may be a solvent-based biocompatible polymer.The dry microporous polymer matrix, or mesh, with embedded gellingpowder structure may additionally be mechanically milled to produceDeconstructed Scaffold Gelling Granule. The step of hydrating may be thestep of implanting the shelf-stable structure having the Gelling Powderand/or the Deconstructed Scaffold Gelling Granule into a patient. Thestep of implanting the dried shelf-stable structure or material mayoccur before the step of activation or gelling. The DeconstructedScaffold Gelling Granules may be further formed by a step of mixing, orcombining, distinct deconstructed scaffold micro-granules. For example,a quantity of Hyaluronic Acid self-gelling micro-granules may be drymixed with a quantity of gelatin or collagen self-gellingmicro-granules, also in dry form. Hydration would occur after drymixing. The method may further comprise the steps of:

-   -   creating a micro-granule embedded gel suspension by hydrating        the gelling powder containing micro-scaffold particles (i.e.,        the structure having a microporous polymer with an embedded        gelling powder); and injecting the solid-gel suspension through        a syringe forming a distinct structure comprising a continuous        hydrogel anchored within and surround distinct units of nano-        and micro-porous biocompatible polymer particles before the step        of washing wherein the gel is microstructurally, or physically,        anchored within the nano- and micro-porous biocompatible polymer        particles after the step of hydrating.

In examples, the micro and nano particles are embedded within themicroporous polymer. The nano particles may be or may comprise a metal,a ceramic, a drug, RNA, DNA, bioactive factor, or other biologicallyrelevant material and the micro particles may be or may comprise ametal, a ceramic, a drug, RNA, DNA, bioactive factor, or otherbiologically relevant material different from the nano particles. In oneexample, the nano particles are metal and the micro particles areceramic and vice versa. In some examples, the above methods may furthercomprise a step of implanting the dry shelf-stable material before thestep of activation or gelling.

The foregoing and other objects, features, and advantages of theexamples will be apparent from the following more detailed descriptionsof particular examples as illustrated in the accompanying drawingswherein like reference numbers represent like parts of the examples.

BRIEF DESCRIPTION OF THE DRAWINGS

Reference is made to the accompanying drawings in which particularexamples and further benefits of the examples are illustrated asdescribed in more detail in the description below, in which:

FIG. 1A is an image of a product of the present disclosure having agelling powder added to a 3D printed ink composition of the productbefore formation and where the product is illustrated before activation,or gelation, in accordance with an example of the disclosure.

FIG. 1B is an image of a product of the present disclosure having agelling powder added to a 3D printing ink composition and that hasundergone activation, or gelation, (after activation, or gelation), suchas a post-printing, or post-processing, rehydration process to form agel that exudes from and surrounds the microporous polymer matrix, ormesh, and is microstructurally, or physically, anchored (within apolymer matrix, or mesh, framework), in accordance with an example ofthe disclosure.

FIG. 2A is a flow diagram of a self-gelling approach (referred to hereinas APPROACH 1) of forming a biocompatible polymer matrix, or mesh, whichdefines a structure of an object that is further encapsulated within agel that is a product of an ink composition comprising a gelling powderhaving been washed through a repeated series of alcohol solution, waterwashes performed after extruding where, due to the highly absorbentnature of the gelling powder, the washing approach will result in thegelling powder absorbing water and gelling to provide the biocompatiblepolymer matrix, or mesh, structure encapsulated within the gel afterextruding, in accordance with an example of the disclosure.

FIG. 2B illustrates images of a product corresponding to the steps ofthe flow diagram of FIG. 2A for a self-gelling approach (referred toherein as APPROACH 1). The representative products of the images are ofthe self-gelling approach of forming a biocompatible polymer matrix, ormesh, which defines a structure of an object that is furtherencapsulated within a gel that is a product of an ink compositioncomprising a gelling powder having been washed through a repeated seriesof alcohol solution, water washes performed after extruding where, dueto the highly absorbent nature of the gelling powder, the washingapproach will result in the gelling powder absorbing water and gellingto provide the biocompatible polymer matrix, or mesh, structureencapsulated within the gel after extruding, in accordance with anexample of the disclosure.

FIG. 3A is a flow diagram of another approach (referred to herein asAPPROACH 2) of forming a biocompatible polymer matrix, or mesh, whichdefines a structure of an object that is further encapsulated within agel that is a product of a gelling powder comprising an ink compositionhaving been washed through an anhydrous washing conducted in a fully orprimarily (>50%) non-aqueous solvent, such as isopropanol, ethanol, orother alcohol-based solution to prevent pre-gelling to provide alyophilized (freeze-dried) gelling powder that may, thereafter, berelied on in a product that may gel upon rehydration in a controlledenvironment to provide the biocompatible polymer matrix, or mesh,structure encapsulated within the gel, in accordance with an example ofthe disclosure.

FIG. 3B illustrates images of a product corresponding to the steps ofthe flow diagram of FIG. 3A (referred to herein as APPROACH 2). Therepresentative products of the images illustrate the forming of abiocompatible polymer matrix, or mesh, which defines a structure of anobject that is further encapsulated within a gel that is a product of agelling powder comprising an ink composition having been washed throughan anhydrous washing conducted in a fully or primarily (>50%)non-aqueous solvent, such as isopropanol, ethanol, or otheralcohol-based solution to prevent pre-gelling to provide a lyophilized(freeze-dried) gelling powder that may, thereafter, be relied on in aproduct that may gel upon rehydration in a controlled environment toprovide the biocompatible polymer matrix, or mesh, structureencapsulated within the gel, in accordance with an example of thedisclosure.

FIG. 4 is a flow diagram of an additional approach (referred to hereinas APPROACH 3) of Dried Gelling Powder Structures, or Gelling Powdercontaining structures, such as extruded fibers, that undergo additionalprocessing (e.g., mechanically milling) to yield deconstructed scaffoldmicro-granules or, in other words, Deconstructed Scaffold GellingGranules. Such a collection of deconstructed scaffold micro-granules or,in other words, Deconstructed Scaffold Gelling Granules would beshelf-stable in dry form, but could be hydrated (see below), resultingin gelling of the powders contained within the particles' polymermatrices lubricating the particles, and create an interconnected networkof discrete micro-granules connected by and suspended within a gelnetwork, as referred to herein as a solid-gel suspension, that iscapable of injection through a syringe. Such a hydrated material couldbe 3D-printed into an additionally distinct material, or structure, (onecomprised of non-continuous distinct units of nano- and micro-porousbiocompatible polymer particles, connected by a gel networkcharacterized by microstructured anchored “points” within eachbiocompatible polymer microparticle), in accordance with an example ofthe disclosure.

FIG. 5A illustrates an image of a scanning electron micrograph of a 3Dprinted fiber interior within a larger 3D printed scaffold comprised ofgelatin self-gelling powders in a porous matrix beforeactivation/gelation (pre-hydration) (left image), in accordance with anexample of the disclosure.

FIG. 5B illustrates an image of a scanning electron micrograph of a 3Dprinted fiber interior within a larger 3D printed scaffold comprised ofgelatin self-gelling powders in a porous matrix afteractivation/gelation (post-hydration) (right image) wherein the porousmicroscaffold 500 is labeled, the gelatin gel 510 is labeled, and thegelatin gel anchored within nano- and micro-porous polymer mesh 520 islabeled, in accordance with an example of the disclosure.

FIG. 6A illustrates an image of a scanning electron micrograph of thecross-sections of a 3D printed fiber interior within a larger 3D printedscaffold comprised of calcium phosphate ceramic spheres and hyaluronicacid self-gelling powders in a porous matrix, or mesh, beforeactivation, or gelation (left image), in accordance with an example ofthe disclosure.

FIG. 6B illustrates an image of a scanning electron micrograph of thecross-sections of a 3D printed fiber interior within a larger 3D printedscaffold comprised of calcium phosphate ceramic spheres and hyaluronicacid self-gelling powders in a porous matrix, or mesh, after activation,or gelation (right image), in accordance with an example of thedisclosure.

FIGS. 7A-7B illustrate images of scanning electron micrographs (detail)of individual deconstructed scaffold micro-granules obtained via millingof larger 3D printed structures. The left granule of FIG. 7A illustratesan individual deconstructed scaffold micro-granule (non-self-gelling)and, specifically, is comprised of a non- and microporouspolylactide-co-glycolide matrix, in accordance with an example of thedisclosure. The right granule of FIG. 7B illustrates an individualhyaluronic acid gelling powder containing deconstructed scaffoldmicro-granule (pre-activation/pre-gelling) and, specifically, iscomposed of dry hyaluronic acid powder embedded within a nano- andmicro-porous PLG matrix, in accordance with an example of thedisclosure.

FIG. 8A illustrates a photograph of a syringe (top image) containing ahydrated (saline) mixture of non-self-gelling deconstructed scaffoldmicro-granules (approximately 33 wt. %) and self-gelling hyaluronic aciddeconstructed scaffold micro-granules (approximately 65 wt. %) prior toextrusion through 22 Ga needle wherein the mixture is capable of beingextruded through the 22 Ga needle, in accordance with an example of thedisclosure.

FIG. 8B illustrates an image of a scanning electron micrograph ofextruded micro-granules (left image), in accordance with an example ofthe disclosure.

FIG. 8C further illustrates an image of a scanning electron micrographof discrete micro-granules interlocked with each-other and connected viaexuded gel wherein gel originating from within the polymer matrixgranules 800 are labeled and biocompatible polymer matrix micro-granulefrom deconstructed scaffold 850 are labeled (right image), in accordancewith an example of the disclosure.

DETAILED DESCRIPTION

The self-gelling materials and structures defined in this invention invarious embodiments offer improved performance over existing gellimitations because, for example, 1) the microstructurally, orphysically, anchored characteristics help localize the gel, and theoverall printed, or otherwise formed structure, give structural form tothe gel—allowing the gel to be localized within the body, and evensutured in place—mitigating gel migration and extending its residencetime; 2) the underlying 3D printed structure helps contain and supportthe gel after implantation; and/or 3) the dried Gelling Powder and/orthe dried Deconstructed Scaffold Gelling Granule containing material isshelf-stable and can be cut, trimmed, compressed, delivered via cannula,etc., for example, prior to hydration—allowing it be placed and hydratedwith surrounding blood, media, plasma, etc. upon implantation—greatlyincreasing the device's ability to integrate and heal surroundingtissue. The presently disclosed structures having one or moreself-gelling components are distinct from injection of an alreadyhydrated gel, which is much slower to absorb surrounding biologicalcomponents because it is already hydrated. Additionally, the underlyingpolymer mesh structures help maintain implant form and localizationbetter than a polymer mesh that has a gel added to it prior toimplantation, where the gel is not microstructurally, or physically,anchored within the microstructure of the polymer network and is insteadjust loosely encapsulating it. FIG. 1A illustrates a material made froman ink comprising a gelling powder, where the material is in a dryshelf-stable state before activation, or gelation. FIG. 1B illustratesan activated self-gelled material made from a gelling powder comprisingink.

In the briefest form, this invention: Solves the problem of hydrogellocalization for medical applications (allowing existing gels to be moreeffective). Specifically, “self-gelling” structure is defined herein asa structure, scaffold, or material that may beimplanted/installed/placed as a dry, structured object into a wound, orbody, or an environment as an implant and upon being exposed to themoisture of the body, or installed environment, at least a portion ofwhich is activated to form a gel encapsulating and anchored within adefined microporous polymer structure. In other words, “self-gelling.”The Gelling Powder within the polymer matrix, or mesh, “activates” byessentially soaking up water (and whatever is in the water such as, forexample, blood cells), sometimes soaking up to 5-times its own weight ormore. The absorption results in a very large volume change and effectivetransformation of dry solid gelling powder particles into expansive, wethydrogel that saturates the nano- and micro-pores of the polymer (i.e.,polyester matrix, or mesh) and ends up exuding beyond the boundaries ofthe polymer component, encapsulating polymer material and generallyencapsulating the larger 3D printed structure.

In this “Activated State” the form of the 3D printed polymer materialremains in its original configuration (although expanded slightly as aresult of the gel expansion pushing on the polymer pore walls from theinside out as gel was forming), acting as a polymeric reinforcement tothe gel.

Three specific application areas, to be used as examples, illustratesthe benefits of the approach of the present disclosure are as follows:

Example 1: Biological joint (osteochondral) repair with 3D-printedhyaluronic acid structures having one or more self-gelling components.In this example, hyaluronic acid (HyAc) is frequently used for treatingdamaged or degraded joints (trauma, arthritis, side effect of surgery,etc.), as it is a naturally present material in cartilaginous jointtissues. For these treatments, HyAc is typically employed as injectablegel or added to an existing implant device and implanted. Although HyAcis compositionally relevant to treating joint disorders, HyAc gelinjections have limited and short-lived impact due the fact that HyAcgel migrates away from the initial injection site as a result of normalbiological movement. This migration also results in the HyAc gelphysically breaking down and not adequately incorporating into orintegrating with the surrounding tissues. This problem is slightlymitigated if the gel is injected into an existing porous structure whichis subsequently implanted; however, the gel is not well integrated withthe porous implant structure and will also begin to migrate away fromthe site because of movement. Additionally, both of these existingapproaches require the gel to be a hydrated gel immediately prior toimplant, limiting the amount of surrounding blood and biological mediathat can be absorbed by the injection or implant. With the currentinvention, a designer structure (whatever shape and form factor isneeded) could be deployed to the desired site via standard or minimallyinvasive or cannulated processes and sutured to surroundingtissues—fixing it into place while the structure is absorbingsurrounding blood, cells, etc., swelling as a result, and further fixingit into place. The resulting gel within the structure ismicrostructurally, or physically, anchored with the polymer meshnetwork, helping to keep it localized even during movement—thusextending its residency time and therapeutic effect.

Example 2: Injectable gels to treat damaged tissues or organs (i.e.,cardiac tissue after infarction). Similar to the previous example, anumber of conditions result in surface or subsurface damage to tissuesand organs—one example being cardiac infarction, whereby cardiac tissuedies. Emerging methods to treat this include injecting hydrogels withdrugs, cells, etc. directly onto the damaged tissue. However, due to thesurface nature of the defect as well as the dynamic nature of the organ,the gel does not stay localized for an extended period of time, limitingits therapeutic potential. For example, a sheet of material having oneor more self-gelling components could be delivered via canula to theheart and fixed (via surgical glue or fine suture) to/around the injurysite. The implant was in the form of the structure having a self-gelduring this process, and the resulting gel would be anchored within thestructural, highly porous polymeric microstructure of thestructure—keeping the implant localized to the desired site.

Example 3: In instances where injectables are still required (minimallyinvasive procedures where larger implants can't be used), themicro-scaffold approach (Approach 3 described below), could be used inplace of directly injecting hydrogel. Although not as effective atlocalizing the gel as a larger structure would be, the existence of themicroparticles and integration with the exuded gels, would help retainthe form and residence time of the injection. One example would be fortreating subsurface spinal cord injuries, whereby an injection ofmicro-scaffold particles into the injury site would result inself-gelling (expanding) therapeutic filler that is anchored to the sitein part due to the connection between the gel and the microporousstructure of the polymer microparticles.

Examples of the present disclosure may be relied on as a uniqueextension of, or improvement to, the ink compositions and/or scaffoldmaterials of U.S. Pat. No. 10,584,254 entitled INK COMPOSITIONS FORTHREE-DIMENSIONAL PRINTING AND METHODS OF FORMING OBJECTS USING THE INKCOMPOSITIONS, filed 14 Nov. 2016, which is herein incorporated byreference in its entirety (hereinafter referred to as the “'254Patent”). The '254 Patent sets forth a (laminarly-extrudable, atroom-temperature, without chemical or thermal reaction) 3D-printable“ink” created from a series of solvents, biocompatible polymer, andparticles/powders. This “ink” can be 3D-printed into a variety of formfactors and is also amenable to other manufacturing methods (such as,for example, fiber forming, textiles, weaving, casting, etc.). While thebasic ink composition approach may rely on compositions of the above'254 Patent, the present disclosure sets forth a post-processablematerial, a process, a means of use, and/or features distinct from thebasic ink composition described in the '254 Patent. Specifically, thepresent disclosure sets forth a Gelling Powder and self-gellingtechnique that is structurally supported by the ink composition and/orscaffold of the '254 Patent while remaining localized, as shown to be adeficiency of the prior art. It is appreciated herein that while the'254 Patent is relied on as an example of an ink composition and/orstructures, or scaffolds, the self-gelling techniques and the GellingPowder of the present disclosure may be relied on as an improvement toother ink compositions and/or structures, or scaffolds, as set forthbelow.

The Powder and the Ink

In the instance of the current invention, an ink, such as that disclosedby the '254 Patent, may comprise one or more of the post-forming powdersthat is a dry (essentially moisture free), hygroscopic, and highlymoisture (water) absorbent material (hereinafter, “Gelling Powder”),that undergoes substantial swelling when exposed to moisture. TheGelling Powder must not be substantially soluble or is non-soluble innon-polar solvents, such as alcohols or dichloromethanes. If theintended use of the ink is for extrusion-based 3D printing, such as thatdisclosed by the '254 Patent, it is preferred that the Gelling Powderhave an average particles size of less than 100 μm to allow forextrusion from a fine tip nozzle and deposition of material.

The Gelling Powder may be synthetic (e.g., Polyethylene glycol,polyethylene oxide, or their variants), natural (gelatin, cellulose,chitosan, alginates, “gums”, hyaluronic acid, other polysaccharides),zeolites, naturally derived (hyaluronic acid and previously mentionedmaterials from bacterial or fungal fermentation) materials,synthetically derived natural materials (synthetically producedcollagen), silicates, silicon-based polymers or combinations thereof Insome examples, the Gelling Powder is capable of retaining via H-Hinteractions (Hydrogen bonding) or electrostatic interactionssignificant volumes of water. Significant may mean equal to or greaterthan the dry mass of the Gelling Powder. For example, 1 gram of dryGelling Powder should be able to retain at least 1 gram of water orother aqueous based solution. The Gelling Powder may be chemicallyfunctionalized (small molecules, drugs, proteins, peptides,nanoparticles, acid group, base group, etc.) prior to use in inksynthesis, provided that the functionalization does not impartsolubility in a non-aqueous solvent, such as alcohol or dichloromethane.The Gelling Powder can exhibit a wide range of average molecularweights, molecular numbers, polydispersities, etc. Molecular weights mayrange from 500 to 5,000,000 Daltons in most examples.

A typical ink, relied on to be used in combination with the GellingPowder, is comprised of a tri-solvent mixture of evaporant (such as forexample dichloromethane), surfactant (such as for example2-butoxyethanol), plasticizer, and polymer. The polymer may be anon-biocompatible polymer such as, for example, one or more ofpolystyrene, polyvinyl alcohol, etc. The polymer may additionally, oralternatively, be a biocompatible polymer such as, for example, one ormore of poly(lactide-co-glycolide) (PLG), polylactide (PLA),polycaprolactone, polyglycolide, etc. The ink of the present disclosuremay additionally, or alternatively, be used with cyclodextrins to adjustthe solubility of the ink composition. The tri-solvent mixture andpolymer and, more specifically, the biocompatible polymer may begenerally the same as previously described in the '254 Patent. A polymermay be added to and dissolved in the evaporant (dissolving slowly underambient conditions). In one specific example, 1 g of polymer is used forevery 2-10 g of evaporant. The evaporant amount may be changed dependingon the desired viscosity of the final ink. The surfactant andplasticizer are added to the evaporant/dissolved polymer. The amount ofsurfactant relative to the evaporant may vary depending on the desiredfinal properties of the ink and the nature of the powder being used.

In the present disclosure, the ink is combined with the Gelling Powderor the ink comprises the Gelling Powder. The combination of the GellingPowder and the ink is a single integrated material. In one example, thepowder component makes up 50-80 vol. % (solids content, polymer+powder).All of the powder components of the resulting ink can be the GellingPowder(s), including multiple distinct Gelling Powders or the powdercomponent can be partially comprised of Gelling Powders and partiallycomprised of non-gelling powders compatible with the underlying inkcomposition (does not dissolve in dichloromethane or similar non-polarsolvents). For example, the ink may contain 35 vol. % Hyaluronic Acid(AKA: sodium hyaluronate—the Gelling powder) and 35 vol. % bioceramic(e.g., calcium phosphate, such as bioceramic). The combination of theink and the powder should be substantially free of water or otheraqueous-based fluids. The inks will rapidly dry and solidify whenexposed to air. The molecular weight of the gelling powder can rangefrom 10,000 kDa to 10,000,000 kDa. In specific examples, the GellingPowder is added last. The ink is physically mixed until it is homogenousat which point it is ready to 3D print via room-temperature extrusion.The resulting 3D printed structure comprise the polymer (which exists asa nano- and micro-porous matrix, in addition to the larger 3D printedmacro form), the powder(s) (embedded within the porous polymer matrix),and residuals of the three solvents (embedded within and on the surfaceof the porous polymer matrix.

Other powders may be added to the ink in addition to the gelling powder.For example, the ink may contain Hyaluronic Acid (HA) gelling powder andhydroxyapatite (HA) bioceramic to yield a final “HAHA” 3D printedmaterial. The Gelling Powder component will turn into a gel and greatlyexpand when exposed to water, and the bioceramic particles can remainwithin the polymer matrix (for example, if they are larger than nano inscale).

In some examples, the powder components of the resulting ink may becomprised of Gelling Powders and electrically conductive materials, suchas graphite, graphene, carbon nanotubes, carbon black, micro or nanodiamonds—this would impart electrical conductivity to the finalfabricated structure. In some examples, the powder components may becomprised of Gelling Powders and biologically derived materials, such ascollagens and tissue-specific decellularized extracellular matrices(e.g., muscle, cartilage, kidney, liver, ovary, skin, fat, etc.)—thiswould impart additional biological properties to the final fabricatedstructure. In yet other examples, the powder components may be comprisedof Gelling Powders, and combination of the previously mentioned types ofpowders, or any powder compatible with the tri-solvent system. Some inkexamples may contain synthetic, natural, hybrid, organic or inorganicnanoparticles (<1 μm) in addition to the Gelling Powders. The GellingPowder containing inks are highly viscous, but able to flow under theirown weight at 1 G. Viscosity may be tailored by altering the amount ofevaporant solvent present in the formulation—more for less viscous inks,less for more viscous inks.

As used herein Gelling Powders are distinguished from gels. A GellingPowder is a highly absorbent solid in powder form. The highly absorbentpowder only becomes a gel upon being exposed to, or mixed with, anaqueous solution, as defined below. What distinguishes the presentdisclosure from prior inks for 3D printing, that may rely on gellingpowders, is that the gelling powder in prior inks are mixed with anaqueous solution as a part of the ink and prior to 3D-printing,extruding, or forming the ink to form a hydrogel structure, scaffold, orproduct. Thereby, the gelling powder of prior inks are, in fact, gels,or in their gel form. In contrast, the Gelling Powder of the presentdisclosure remains as a Gelling Powder, or solid, within the ink, andthrough the ink extrusion process, by way of the non-aqueoussolvent-based nature of the ink composition. The Gelling Powder of thepresent disclosure does not become a gel until after 3D printing,extrusion, or forming has been completed and by way of a post-processingtreatment. The ink does not comprise a gel. In other words, the GellingPowder does not become a gel until a post-processing treatment isengaged on the structure, scaffold, or product formed from the ink, suchas that described by Approaches 1-3, and the corresponding aqueous basedcompositions for gelling.

In terms of processing, the bio-compatible polymer is added to anddissolved in the evaporant. Typically, lg of polymer is used for every2-10 g of evaporant (evaporant amount can be changed depending ondesired viscosity of final ink). The surfactant and plasticizer areadded to the evaporant/dissolved polymer. Amounts relative to evaporantcan vary depending on desired final properties of the ink and nature ofpowder being used. The gelling powder and any other desired powder(s)are added last—typically added such that the gelling powder and make up85 vol. % or less of the total solids volume of the ink (polymer+powdervolume). In some examples, the gelling powder make up 1-85 vol. % of thetotal solids volume of the ink (polymer+powder volume). In yet otherexamples, the gelling powder make up 50-85 vol. % of the total solidsvolume of the ink (polymer+powder volume). This is physically mixeduntil homogenous at which point it is ready to 3D print via simpleroom-temperature extrusion.

3D-Printing and Forming

Gelling Powder containing inks are 3D-printed, or otherwise formed,using processes previously described in the '254 Patent. In brief,Gelling Powder containing inks are laminarly extruded atroom-temperature via pneumatic, piston, or auger driven mechanisms.Within milliseconds after extrusion from fine tipped nozzles (100-1000μm), the Gelling Powder containing ink solidifies and is capable ofsupporting its own weight upon deposition onto a substrate whilemaintaining the Gelling Powders as a solid and not a gel. The substratemay be any material, including previously deposited Gelling Powdercontaining inks. Through this process, layers of Gelling Powdercontaining inks can be deposited to created solid structures comprisedof fibers (or filaments). Other use of the inks includes extrusion andcollection of fibers/filaments. The fibers are flexible and can be usedas is or further processed via braiding, cabling, weaving, or othertextile methods. Other uses of the inks include casting onto orinjecting into a flat, textured, or volumetric mold. Regardless offabrication method, the resulting Gelling Powder containing structuresmust be washed to remove residual solvents. Additionally, oralternatively, the Gelling Powder containing inks is furtherincompatible with any process that requires significant thermal energyadditions such as, for example, heating, melting, or the like as thedried gelling powder material would likely degrade.

The resulting 3D printed structures are comprised of: The polymer(exists as nano- and micro-porous matrix, or mesh, in addition to thelarger 3D printed macro form); the powder(s)—embedded within the porouspolymer matrix, or mesh; residuals of the three solvents -embeddedwithin and on the surface of the porous polymer matrix, or mesh. As usedherein, “embedded” or “embedded within” is defined as being integratedinto the microstructure of a material or being microstructurally, orphysically, anchored.

Residuals of the solvents may be removed via an alternating series ofalcohol solution and water washes or through washing in only an alcoholsolution. In the alternating series of alcohol solution and water washexample, exposure to water (or majority water solution) will initiateactivation and gelation of the Gelling Powder component prior to thedrying step. After drying, the structure may be rehydrated upon exposureto sufficient liquid. In the alcohol solution only washing example,activation and gelation does not occur before the drying step. Afterdrying, when pre-activation of the Gelling Powders is desired, exposureto water (or majority water solution or liquid/water environment) wouldcause the Gelling Powder (embedded within the polymer component) to gel.Comparatively, washing may be carried out in majority alcohol solutionswhen activation/gelling before drying is to be avoided.

Post-3D-Printing and Forming Processing

Post-forming, Gelling Powder containing structures, or structures formedfrom an ink where the Gelling Powder is maintained as a gelling powder,or a solid, and not a gel, must be washed and dried.

Approach 1 (See FIGS. 2A-2B)

As illustrated by the steps of FIG. 2A, and the products illustrated byFIG. 2B corresponding to the respective steps of FIG. 2A, Gelling Powderstructures may be washed through a repeating series of alcohol solution,water washes. The alcohol and water washes are provided to removeresidual solvents (manufacturing residuals) from the structure. Due tothe highly absorbent nature of the Gelling Powder, this washing approachwill result in the Gelling Powder being activated by absorbing water andgelling—resulting in biocompatible polymer matrix, or mesh, defining theoverall structure of the object, encapsulated within and permeated by agel. The drying step after washing places the material, or structure ofthe object, into a shelf-stable form. As used herein “shelf-stable” isdefined as being dry, dehydrated, or dried to form a material that maybe cut, trimmed, compressed, delivered via cannula, etc., for example,prior to hydration, or subsequent processing. In other words, ashelf-stable structure is capable of being placed and hydrated withsurrounding blood, media, plasma, etc. upon implantation—greatlyincreasing the device's ability to integrate and heal surrounding tissue(distinct from injection of an already hydrated gel, which is muchslower to absorb surrounding biological components because it is alreadyhydrated). A final hydration step as outlined by the AQUEOUS-BASEDCOMPOSITIONS FOR GELLING, below, is provided as the final use processingof the material, or structure of the object.

Approach 2 (See FIGS. 3A-3B)

Due to the highly absorbent (aqueous) nature of the Gelling Powdermaterials, washing may be conducted in a fully or primarily (>50%)non-aqueous solvent, such as isopropanol, ethanol, or otheralcohol-based solutions in order to prevent pre-gelling if desired, asillustrated by the steps of FIG. 3A, and the products illustrated byFIG. 3B corresponding to the respective steps of FIG. 3A. In otherwords, the Gelling Powder structure is not washed using an aqueous orprimarily aqueous solution (e.g., water) but, instead, is washed using anon-aqueous solvent to prevent activation of the Gelling Powder. Incontrast, if exposed to an aqueous or primarily aqueous solution, thestructure will gel as it does under APPROACH 1, above. This approachimparts a substantial modification to the ink composition of the '254Patent which requires the structures to otherwise be exposed to water.

Under either approach, washing times and volume of wash media will varydepending on the size and exposed surface area of the object beingwashed. Typically wash times range from 5-120 minutes. Multiple washcycles may be used. Post-washing drying can be achieved through anysingle or combination of multiple means. In one example, the GellingPowder structure, or Gelling Powder containing object, that has beenwashed in primarily alcohol solution can be air dried or dried withflowing air (fan, compressed air, etc.) assistance. In another example,the Gelling Powder structure, or Gelling Powder containing object, thathas been washed in primarily alcohol solution can be lyophilized(freeze-dried). However, due to the high alcohol content, the user mustensure that the lyophilizer used is capable of condensing (freezing) thesolution used to wash the Gelling Powder structure, or Gelling Powdercontaining object. In another example, the Gelling Powder structure, orGelling Powder containing object, that has been washed in alcoholsolution can be critically point dried using super critical CO₂ atappropriate pressures and temperatures. It is critical that any objectgoing through critical point drying be substantially free of water priorto critical point drying. The resulting dried, Gelling Powder structure,or Gelling Powder containing object, should be shelf stable as long asit is stored in a moisture free environment (desiccator, hermeticallysealed packaging, etc.) at temperatures typically lower than 60°Celsius. The resulting dried, Gelling Powder, or Gelling Powdercontaining object, can be described as a composite of biocompatiblepolymer and distinct particles of embedded Gelling Powder. Thebiocompatible polymer component is typically microporous, and could bedescribed as a disordered, interconnected mesh network. Within the meshnetwork, Gelling Powder particles are trapped, and the fabricatedstructures do not contain any gel or substantial amount of moisture(e.g., they are solid materials, not gel or liquid). Thereafter, theGelling Powder particles may be activated, or hydrated, as outlined bythe AQUEOUS-BASED COMPOSITIONS FOR GELLING, below.

With respect to APPROACHES 1-2, above, dry Gelling Powders may be usedwith and/or 3D printed into additionally distinct material/structuressuch as those described in: U.S. Pat. No. 9,327,448 entitled METHODS FORFABRICATING THREE-DIMENSIONAL METALLIC OBJECTS VIA ADDITIVEMANUFACTURING USING METAL OXIDE PASTES, filed 1 Aug. 2014; U.S. Pat.tNo. 10,236,528 entitled THREE DIMENSIONAL EXTRUSION PRINTEDELECTROCHEMICAL DEVICES, filed 18 Jul. 2016; U.S. Pat. No. 10,350,329entitled GRAPHENE-BASED INK COMPOSITIONS FOR THREE-DIMENSIONAL PRINTINGAPPLICATIONS, filed 15 Oct. 2015; U.S. Pat. No. 10,793,733 entitled INKCOMPOSITIONS FOR FABRICATING OBJECTS FROM REGOLITHS AND METHODS OFFORMING THE OBJECTS, filed 7 Apr. 2016; U.S. Patent Publication No.2019/0343989 A1 entitled SURGICALLY-FRIENDLY TISSUE PAPERS FROMORGAN-SPECIFIC DECELLULARIZED EXTRACELLULAR MATRICES, filed 16 May 2019;and U.S. Patent Publication No. 2020/0353129 A1 entitled WATER-SOLUBLESALT PARTICLE CONTAINING COMPOSITIONS AND POROUS MATERIALS MADETHEREFROM, filed 29 Apr. 2020; all of which are herein incorporated byreference in their entirety.

APPROACH 3 (See FIG. 4 )

Dried Gelling Powder Structures, or Gelling Powder containingstructures, such as extruded fibers, can undergo additional processingto yield gelling powder containing, deconstructed scaffoldmicro-granules or, in other words, Deconstructed Scaffold GellingGranules. Specifically, dry Gelling Powder Structures, or Gelling Powdercontaining structures, can be mechanically milled (cutting mill) andsieved to yield powders with individual particle composition andmicrostructure representative of a larger 3D printed or otherwise formedGelling Powder Structure, or Gelling Powder containing structure. Such acollection of gelling powder containing, deconstructed scaffoldmicro-granule powders would be shelf-stable in dry form, but could behydrated (see below), resulting in gelling of the powders containedwithin the particles' polymer matrices lubricating the particles, andcreate an interconnected network of discrete microgranules connected byand suspended within a gel network that is capable of extrusion througha syringe. Such a hydrated material could be 3D printed into anadditionally distinct material/structure (one comprised ofnon-continuous distinct units of nano- and micro-porous biocompatiblepolymer particles, connected by a gel network characterized bymicrostructured anchored “points” within each biocompatible polymermicroparticle). The term “Deconstructed Scaffold Gelling Granules”, asdefined herein, refers to the product resulting from milling, notbefore. In other words, 3D printed, extruded or otherwise formedproducts may be additionally milled to yield powders, with each powderparticle having a composition and microstructure representative of thepre-milled material. The Deconstructed Scaffold Gelling Granules arethose structures created from those powders yielded from the milledextruded, or otherwise formed, products. Milling a large volume ofmaterial makes powders from that material and each powder particle is,essentially, a tiny version of that larger structure which was milled.Thereby, each particle contains a composite of some gelling powder,polymer, and any other powder that may have been in the originalmaterial or ink. Further, milled powders may also be sieved and sortedto obtain specific size ranges if desired. Micro-granules are typicallygreater than 20 μm in size. In one particular example, for cell deliveryand tissue repair applications, it may be important that themicro-granules be several times larger than the majority of theimmediately adjacent or adherent cells. This size difference promotesinteraction of individual cells with individual micro-granules in amanner similar to individual cells interacting with a much largerstructure comprised of the same material and defined by the samemicrostructure as the micro-granules.

APPROACH 3 is further illustrated by FIG. 4 . In FIG. 4 , a 3D printedstructure comprising a dry gelling powder embedded within a porouspolymer matrix, or mesh, structure, as formed by either APPROACH 1 or 2above (Step 1 of FIG. 4 ), may be mechanically milled to formshelf-stable Deconstructed Scaffold Gelling Granule which arerepresentative of the components of the original larger structure (Step2 of FIG. 4 ). The mechanically milled Deconstructed Scaffold GellingGranules may be combined with an aqueous solution (e.g., blood, water,etc.), thereby, activating/gelling the Gelling Powder component of theDeconstructed Scaffold Gelling Granules to form an activated/gelledscaffold suspension of the Deconstructed Scaffold Gelling Granules (Step3 of FIG. 4 ). The micro-granule particles of the scaffold suspension ofthe Deconstructed Scaffold Gelling Granules are anchored, yet also aflowable, gel-particle suspension upon gelation. The suspension may beloaded into a syringe and injected into or onto a site such as, forexample, tissue, organ, or wound site (Step 4 of FIG. 4 ). Accordingly,the Deconstructed Scaffold Gelling Granules may be further utilized as agelling powder of either APPROACH 1 and 2.

As used herein in view of the above approaches, the washed structure isdried to obtain its “shelf-stable” state. Drying may be done via anynumber of methods, including: Air drying (with or without aid, such as afan); critical point drying; lyophilization. The dried structure may nowbe comprised only of, consist of, or consist essentially of the nano-and micro-porous polymer matrix, or mesh, with embedded Gelling Powdersand/or Deconstructed Scaffold Gelling Granules (and other powders ifthey were added). The dry structures may be flexible and are capable ofbeing cut with a scissors, razor blade, or equivalent sharp tool. Thedry structures may also be capable of holding a suture or a thread. Thedry structures, when in thin (sheet or membrane-like form) may also becompressed and pushed down a cannula.

As also used herein in view of the above approaches, upon exposure tosufficient water, the Gelling Powders and/or the Deconstructed ScaffoldGranules, within the polymer matrix, or mesh, “activates”—essentiallysoaking up more than 5 times its own weight in water (and whatever is inthe water . . . i.e., blood). The absorption results in a very largevolume change and effective transformation of dry solid gelling powderparticles into expansive, wet hydrogel that saturates the nano- andmicro-pores of the polymer (i.e., polyester) matrix, or mesh, and endsup exuding beyond the boundaries of the polymer component, encapsulatingpolymer material and generally encapsulating the larger 3D printedstructure.

Aqueous-Based Compositions for Gelling

Gelling Powder containing washed and dried structures are capable ofexuding “microstructurally anchored” or “physically anchored” gel uponexposure to aqueous based liquids, as illustrated by both FIGS. 2A, 2B,3A, and 3B. Essentially, the distinct, dry Gelling Powders and/orDeconstructed Scaffold Gelling Granules, within the biocompatiblepolymer matrix, or mesh, absorb the water (and anything within thewater) and begin expanding as they transform into a hydrogel (mostlywater containing material, with a minority, interconnected solid polymernetwork—“mostly” being defined as >50% by volume). This process isreferred to, herein, as “activation” of the Gelling Powders and/orDeconstructed Scaffold Gelling Granules. This expansion results inpressure on the surrounding biocompatible polymer matrix, or mesh,network, and exuding or expulsion of the now interconnected gel networkfrom the still solid, highly porous, biocompatible polymer network. As aresult of the expanding gel pressure on the encompassing biocompatiblepolymer, solid mesh network, the mesh network expands, resulting in amacroscopic expansion of the fabricated object (typically, 0.5 to 20%linear expansion in all directions). The gel volume increases to such adegree as a result of exposure to an aqueous based solution that the gelnetwork exudes beyond the boundaries/radius of printed, or otherwiseformed, biocompatible polymer mesh network—resulting in a structure thatcan be described as a highly porous, but solid, polymer mesh networkembedded within a gel. Importantly, the polymer mesh network is not onlyembedded within the gel, but the gel is embedded within the polymer meshnetwork (e.g., the nano- and micro-pores of the polymer network). Thishas important implications for properties and use, as the gel ismicrostructurally, or physically, anchored to/within the structural,porous biocompatible polymer component. Upon activation, thepost-processing treatment of transitioning the Gelling Powder and/orDeconstructed Scaffold Gelling Granule to a gel exuded from within thematerial, or structure, (i.e., inside out gelation). This is in contrastto adding a gel to or adhering a gel to an existing surface (i.e.,outside in) such as that taught by U.S. Publication No. 2019/0060516which adds a gel to an existing surface. It has been found that gelsthat are independent of a structure shear and migrate, or move. Incontrast, the activated gels of the present disclosure which areanchored in the structure, scaffold, or product, as described herein, donot shear or migrate or do not shear or migrate to such a degree. Inother words, the gels, which exude from within the material, orstructure, have an anchor point as opposed to those gels which are addedto a pre-existing material, or structure such that if a shear force isapplied to the gel that is exuding from the nano- and micro-porouspolymer matrix, or mesh, and then released, the gel moves back to itsoriginal position (like it is stuck or anchored within the moresubstantial nano- and micro-porous polymer matrix, or mesh). This limitsgel migration and increases residence time of the gel when it isimplanted in this 3D printed form, relative to the gel just beinginjected or the gel being subsequently added to an existing (3D printedor not) structure.

In another example of the present disclosure, the previously describedinks with a powder component may be a combination of one or more ofGelling Powder, Deconstructed Scaffold Gelling Granule, micro-scale(1-100 micrometer on average) non-gelling powder particles, andnano-scale (0.001 to 0.999 micrometer on average) non-gelling particles.The micro-particles may be comprised of any material that is notsubstantially soluble, or insoluble, in dichloromethane, including butnot limited to: ceramics, metals, alloys, covalent solids, biologicalparticles (extracellular matrix, collagens, proteins), or modifiedparticles thereof. Modifications may include, but are not limited to,surface functionalization, coating, and encapsulation with othermaterials. The nano-scale particles maybe include similar categories ofmaterials of the micro-scale particles, in addition to proteins, drugs,peptides, bioactive factors.

The dry Gelling Powder and/or Deconstructed Scaffold Gelling Granulecontaining structure can be hydrated/gelled with any number of aqueousbased solutions. This includes but is not limited to the following:water, saline, blood, blood plasma, refined blood products (plateletrich plasmas), water-based solutions containing cells, drugs, proteins,peptides, cell or tissue culture media, small molecules, nanoparticles,antibiotics, antimycotics, etc.. The rate of hydration and degree ofgelation (i.e., how much gel is exuded from the polymer network) dependson multiple factors including but not limited to: relatively vol. %Gelling Powder and/or Deconstructed Scaffold Gelling Granule instructure (relative to other powders as well as to the polymercomponent), molecular weight and polydispersity of the Gelling Powderand/or Deconstructed Scaffold Gelling Granule material, aqueous solutionused for gelation. In this way, gelation can be controlled to regulatethe gel “radius” around the biocompatible polymer fibers or largestructures (i.e., small amounts of Gelling Powder and/or DeconstructedScaffold Gelling Granule could result in a gelling radius around theprinted fibers of —10-100 μm or extend several millimeters).

The dry Gelling Powder and/or Deconstructed Scaffold Gelling Granulecontaining structures are typically flexible, depending on the formfactor, and can be elastically and plastically deformed (bent, folded,etc.), cut, stamped, and otherwise trimmed to shape. These processes canalso be performed after the structure has been hydrated and gelled.

Hydrated and gelled structures can optionally be lyophilized (freezedried), resulting in a moisture free structure defined by the originalbiocompatible polymer mesh network embedded within a dried gel network(and the dried gel network also inside the polymer mesh microstructure).

While this invention has been described with reference to examplesthereof, it shall be understood that such description is by way ofillustration only and should not be construed as limiting the scope ofthe claimed examples. Accordingly, the scope and content of the examplesare to be defined only by the terms of the following claims.Furthermore, it is understood that the features of any example discussedherein may be combined with one or more features of any one or moreexamples otherwise discussed or contemplated herein unless otherwisestated.

What is claimed is:
 1. A 3D printed structure having one or moreself-gelling components, the 3D printed structure comprising: a drygelling powder embedded within a porous polymer matrix structureconfigured to form a gel when contacted with an aqueous solution causingit to gel.
 2. The structure of claim 1, further comprising micro andnano particles embedded within the porous polymer matrix structure,wherein the micro and nano particles are one or more of electricallyconductive materials, ceramic materials, metallic materials, andbiologically derived materials.
 3. The structure of claim 1, wherein thepolymer matrix structure comprises a biocompatible polymer.
 4. Thestructure of claim 3, wherein the gel is physically anchored within amicrostructure of the biocompatible polymer matrix structure.
 5. An inkcomposition for printing a 3D printed structure having one or moreself-gelling components, the ink composition comprising: a solvent-basedpolymer extrusion comprising and maintaining a dry gelling powder thatis encapsulated, or integrated, within the polymer that is configured tobe washed in dried alcohol and a water wash after extrusion, remainshelf-stable and in a dry form upon drying after extrusion, and gel uponhydration in an aqueous based solution after extrusion.
 6. The inkcomposition of claim 5, wherein the ink composition is not and does notcomprise a gel.
 7. The ink composition of claim 5, wherein the drygelling powder has an average particle size of less than 100 μm.
 8. Theink composition of claim 5, wherein an additional powder componentcomprising one or more of nano-scale and micro-scale materials that areone or more of electrically conductive materials, ceramic materials,metallic materials, and biologically derived materials suspended in thesolvent-based polymer extrusion.
 9. A method of forming a polymerstructure with one or more self-gelling components comprising the stepsof: combining a solvent-based polymer with a dried gelling powder toform an ink and extruding the ink to form a structure having amicroporous polymer matrix with an embedded dried gelling powder;washing the structure having the microporous polymer matrix with theembedded gelling powder structure through a series of alcohol solutionand water washes to remove residual solvents; activating and gelling thedried gelling powder in the step of washing where the dried gellingpowder absorbs water transforming the dried gelling powder into a gelwhich fills, exudes from, and encapsulates the microporous polymermatrix; drying the gel containing and encapsulating the microporouspolymer matrix into a shelf-stable structure and in a dry form; andhydrating the shelf-stable structure in an aqueous based solution. 10.The method of claim 9, wherein the solvent-based polymer is abiocompatible polymer.
 11. The method of claim 9, wherein the driedgelling powder is mechanically milled to produce a gelling powder havingdeconstructed scaffold micro-granule particles.
 12. The method of claim9, further comprising the steps of: creating a micro-granule embeddedgel suspension from an interconnected network of discrete micro-granulesconnected by and suspended within a gel network by hydrating thestructure having a microporous polymer matrix with an embedded driedgelling powder; injecting the micro-granule embedded gel suspensionthrough a syringe forming a distinct structure comprising a continuousgel anchored within and surround distinct units of nano- andmicro-porous polymer particles before the step of washing and whereinthe gel is physically anchored within the nano- and micro-porous polymerparticles after the step of hydrating.
 13. The method of claim 9,wherein the step of hydrating is a step of implanting the shelf-stablestructure into a patient.
 14. A 3D printed structure having one or moreself-gelling components, the 3D printed structure comprising: a polymermatrix structure encapsulating, or integrating, an anhydrous washed andabsorbent dry gelling powder of discreate, dry particles that areconfigured to form a gel in an aqueous based solution.
 15. The structureof claim 14, wherein the gel from the gelling powder is configured to beanchored within a microstructure of the polymer matrix structure upongelation.
 16. The structure of claim 14, further comprising a network ofmicro and nano particles configured to be embedded within the porouspolymer matrix structure by being encapsulated in a solid-gel suspensionencapsulated, or integrated, within the polymer matrix structure upongelation.
 17. The structure of claim 14, wherein the polymer matrixstructure comprises a biocompatible polymer.
 18. The structure of claim14, wherein the structure is not and does not comprise a gel.
 19. An inkcomposition for printing a 3D printed structure having one or moreself-gelling components, the ink composition comprising: a solvent-basedpolymer encapsulating, or integrating, an anhydrous washed and absorbentdry gelling powder of discreate, dry, particles that are lyophilizedwherein the gelling powder is configured to gel in an aqueous basedsolution after extrusion.
 20. The ink composition of claim 19, furthercomprising micro and nanoparticles configured to be embedded within aporous polymer matrix structure formed from the solvent-based polymer bybeing encapsulated in a solid-gel suspension encapsulated, orintegrated, within the polymer matrix structure upon gelation.
 21. Theink composition of claim 19, wherein the solvent-based polymer is asolvent-based biocompatible polymer.
 22. The ink composition of claim19, wherein the ink composition is not and does not comprise a gel. 23.The ink composition of claim 19, wherein the dry gelling powder has anaverage particle size of less than 100 μm.
 24. The ink composition ofclaim 19, wherein powder components of one or more of electricallyconductive materials or biologically derived materials are additionallyencapsulated, or integrated, in the solvent-based polymer.
 25. A methodof forming a polymer structure with one or more self-gelling componentscomprising the steps of: combining a solvent-based polymer with a driedgelling powder to form an ink and extruding the ink to form a structurehaving a microporous polymer with a gelling powder; washing thestructure having the microporous polymer with an embedded gelling powderin a non-aqueous solvent or anhydrous wash to prevent pre-gelling;drying the washed structure having microporous polymer with embeddedgelling powder to form a dried shelf-stable structure; and activatingand gelling the dried gelling powder of the dried shelf-stable structureby hydrating the dried shelf-stable structure in an aqueous basedsolution where the gelling of the dried gelling powder absorbs water,gels, and expands the microporous polymer matrix of the driedshelf-stable structure.
 26. The method of claim 25, wherein thesolvent-based polymer is a solvent-based biocompatible polymer.
 27. Themethod of claim 25, wherein the dried shelf-stable structure ismechanically milled to produce gelling powder containing deconstructedscaffold micro-granule particles.
 28. The method of claim 22, furthercomprising the steps of: creating a micro-granule embedded gelsuspension by hydrating the structure having the microporous polymerwith an embedded gelling powder; and injecting the micro-granuleembedded gel suspension through a syringe forming a distinct structurecomprising distinct units of nano- and micro-porous polymer particlesbefore the step of washing wherein the nano- and micro-porous polymerparticles are microstructurally anchored within a gel network of thedistinct structure after the step of hydrating.
 29. The method of claim25, further comprising a step of implanting the dried shelf-stablematerial before the step of activation or gelling.
 30. The method ofclaim 28, further comprising a step of implanting the dried shelf-stablematerial before the step of activation or gelling.
 31. The method ofclaim 25, wherein micro and nano particles are embedded within themicroporous polymer matrix.
 32. The method of claim 30, wherein the nanoparticles are a metal, ceramic, drug, bioactive factor, or otherbiologically relevant material and the micro particles are or comprise ametal, ceramic, drug, RNA, DNA, bioactive factor, or other biologicallyrelevant material different from the nano particles.